Bottom Line:
Phosphodiesterase 4B has constituted an interesting target for drug development.In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents.In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

ABSTRACTPhosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

Figure 4: Structures of various congeners of 1-benzothiophene-3-carboxamides with PDE4B inhibitory activity

Mentions:
By high throughput screening, tetrahydrobenzothiophene (THBT) bisamide (10) (Figure 4) was discovered to be a potent and modest PDE4B over the 4D-selective inhibitor (PDE4B/4D pIC50 6.7/6.5) [40]. Authors investigated the HBT binding mode with the ligand/PDE4B catalytic domain of the available co-crystal structure (PBD ID: 3HMV) [41] to design the analogue having PDE4B selectivity over PDE4D. Furthermore, based on the binding mode at the active site of PDE4B, disubstituted-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamides 11 (Figure 4) were synthesized and evaluated for their binding affinity to the PDE4B isoenzyme. Authors disclosed the structure-activity relationship at 3-carboxy and around the tetrahydrobenzo groups. Potencies significantly reduced when the primary amide was methylated and indicated a clear requirement for the primary carboxamide at third position. Structural modification around the tetrahydrobenzo group confirmed the 4B-subtype selectivity and indicated a preference for small C6 substituents. Moreover, the maximum potency and 10-fold selectivity was observed in the compound where R2 = 6-ethyl.

Figure 4: Structures of various congeners of 1-benzothiophene-3-carboxamides with PDE4B inhibitory activity

Mentions:
By high throughput screening, tetrahydrobenzothiophene (THBT) bisamide (10) (Figure 4) was discovered to be a potent and modest PDE4B over the 4D-selective inhibitor (PDE4B/4D pIC50 6.7/6.5) [40]. Authors investigated the HBT binding mode with the ligand/PDE4B catalytic domain of the available co-crystal structure (PBD ID: 3HMV) [41] to design the analogue having PDE4B selectivity over PDE4D. Furthermore, based on the binding mode at the active site of PDE4B, disubstituted-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamides 11 (Figure 4) were synthesized and evaluated for their binding affinity to the PDE4B isoenzyme. Authors disclosed the structure-activity relationship at 3-carboxy and around the tetrahydrobenzo groups. Potencies significantly reduced when the primary amide was methylated and indicated a clear requirement for the primary carboxamide at third position. Structural modification around the tetrahydrobenzo group confirmed the 4B-subtype selectivity and indicated a preference for small C6 substituents. Moreover, the maximum potency and 10-fold selectivity was observed in the compound where R2 = 6-ethyl.

Bottom Line:
Phosphodiesterase 4B has constituted an interesting target for drug development.In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents.In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

ABSTRACTPhosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.